experiment Live Nation CEO Outlines Reopening Strategy: Experimenting with Shows In The Fall, Be On Sale in Q3/Q4, Full Scale By 2021 By feedproxy.google.com Published On :: Fri, 08 May 2020 19:46:15 +0000 It's going to be a little bit until the big shows. The post Live Nation CEO Outlines Reopening Strategy: Experimenting with Shows In The Fall, Be On Sale in Q3/Q4, Full Scale By 2021 appeared first on Metal Injection. Full Article It's Just Business coronavirus Covid-19 live nation
experiment Students Experimenting With Power Of Future By bernews.com Published On :: Fri, 29 Jun 2018 12:20:22 +0000 Two science students have calculated that their school has made huge strides in helping the environment by installing solar panels. About 18 months ago Saltus Grammar School erected a solar system on one of its roofs and students Maximo Deiros, aged 14, and Themika Thennakoon, aged 13, said they have calculated the 97,000 kWh generated […](Click to read the full article) Full Article All Environment News #Education #SolarEnergy
experiment How to test length contraction by experiment? By feedproxy.google.com Published On :: Mon, 17 Jun 2019 14:22:10 +0000 Relativistic length contraction is theoretically predicted but not directly tested, which lead to incorrect interpretation of the theory illustrated by Bell’s spaceship paradox and Ehrenfest paradox. But these paradoxes can help us designing experiments to test length contraction. Ideal direct experimental proof should contain the following steps: 1. Measure the tested object’s length at rest,... Full Article SFN Blogs Uncategorized
experiment From Michelson–Morley experiment to length contraction By feedproxy.google.com Published On :: Thu, 29 Aug 2019 23:00:32 +0000 Length contraction is used to explain Michelson–Morley experiment. A Michelson interferometer is formed by 2 perpendicular arms. The journey of light along the vertical arm gives the time dilation law. The journey of light along the horizontal arm gives the length contraction law. The derivation scheme of the length contraction law is: 1. The time... Full Article SFN Blogs Uncategorized
experiment Length, distance and Michelson–Morley experiment By feedproxy.google.com Published On :: Fri, 14 Feb 2020 11:31:59 +0000 There are 2 types of length contraction, the physical meaning of each is explained below with the help of the example shown in Figure 1. The Earth and the star are stationary and the spaceship mobile. The 2 types of length contraction are: 1) Object contraction: In the frame of the Earth the length of... Full Article SFN Blogs Uncategorized
experiment Experimentando Doces: Dubai e Tailândia By cozinhadobomgosto.com Published On :: Tue, 28 Apr 2020 22:00:24 +0000 Vem dar risada com a gente neste quadro “Experimentando Doces Gringos”! ???? Desta vez provamos doces de Dubai e Tailândia! Entre eles está um dos meus doces industrializados favoritos! Assista e veja se você também fica com água na boca! O post Experimentando Doces: Dubai e Tailândia apareceu primeiro em Cozinha do Bom Gosto. Full Article DESTAQUE Variedades Vídeos doces dubai experimentando provando tailândia
experiment ODA designs an urban experiment masterplan for Chengdu By inhabitat.com Published On :: Tue, 28 Apr 2020 17:30:00 +0000 On the invitation of the Chengdu government, New York-based architecture firm ODA has created a visionary new masterplan for the southwestern Chinese city. Spanning 1 million square feet, the proposal would include four 13-story residential towers integrated into a 700,000-square-foot, mixed-use commercial park with modern buildings optimized for passive energy savings. Described by the firm as an “urban experiment in rearranging priorities for the public realm,” the masterplan emphasizes pedestrian-friendly design and indoor-outdoor living throughout.[...] Full Article Architecture Urban design Green Roof Urban Farming urban planning public space passive solar energy Chengdu pedestrian friendly masterplan mixed-use smart design terrace terraced garden oda
experiment Tesla's Smart Summon is a glitchy 'science experiment,' Consumer Reports says By www.latimes.com Published On :: Wed, 9 Oct 2019 14:48:42 -0400 Smart Summon, the feature that lets Teslas drive themselves through parking lots, is drawing increasing criticism. Full Article
experiment Selection of features with consistent profiles improves relative protein quantification in mass spectrometry experiments By feedproxy.google.com Published On :: 2020-03-31 Tsung-Heng TsaiMar 31, 2020; 0:RA119.001792v1-mcp.RA119.001792Research Full Article
experiment Acquiring and Analyzing Data Independent Acquisition Proteomics Experiments without Spectrum Libraries By feedproxy.google.com Published On :: 2020-04-20 Lindsay K PinoApr 20, 2020; 0:P119.001913v1-mcp.P119.001913Perspective Full Article
experiment Multiple hypothesis testing in proteomics: A strategy for experimental work [Invited] By feedproxy.google.com Published On :: 2010-12-07T11:37:01-08:00 In quantitative proteomics work, the differences in expression of many separate proteins are routinely examined to test for significant differences between treatments. This leads to the multiple hypothesis testing problem: when many separate tests are performed many will be significant by chance and be false positive results. Statistical methods such as the false discovery rate (FDR) method that deal with this problem have been disseminated for more than one decade. However a survey of proteomics journals shows that such tests are not widely implemented in one commonly used technique, quantitative proteomics using two-dimensional electrophoresis (2-DE). We outline a selection of multiple hypothesis testing methods, including some that are well known and some lesser known, and present a simple strategy for their use by the experimental scientist in quantitative proteomics work generally. The strategy focuses on the desirability of simultaneous use of several different methods, the choice and emphasis dependent on research priorities and the results in hand. This approach is demonstrated using case scenarios with experimental and simulated model data. Full Article
experiment Selection of features with consistent profiles improves relative protein quantification in mass spectrometry experiments [Research] By feedproxy.google.com Published On :: 2020-03-31T13:35:14-07:00 In bottom-up mass spectrometry-based proteomics, relative protein quantification is often achieved with data-dependent acquisition (DDA), data-independent acquisition (DIA), or selected reaction monitoring (SRM). These workflows quantify proteins by summarizing the abundances of all the spectral features of the protein (e.g., precursor ions, transitions or fragments) in a single value per protein per run. When abundances of some features are inconsistent with the overall protein profile (for technological reasons such as interferences, or for biological reasons such as post-translational modifications), the protein-level summaries and the downstream conclusions are undermined. We propose a statistical approach that automatically detects spectral features with such inconsistent patterns. The detected features can be separately investigated, and if necessary removed from the dataset. We evaluated the proposed approach on a series of benchmark controlled mixtures and biological investigations with DDA, DIA and SRM data acquisitions. The results demonstrated that it can facilitate and complement manual curation of the data. Moreover, it can improve the estimation accuracy, sensitivity and specificity of detecting differentially abundant proteins, and reproducibility of conclusions across different data processing tools. The approach is implemented as an option in the open-source R-based software MSstats. Full Article
experiment Acquiring and Analyzing Data Independent Acquisition Proteomics Experiments without Spectrum Libraries [Perspective] By feedproxy.google.com Published On :: 2020-04-20T11:35:14-07:00 Data independent acquisition (DIA) is an attractive alternative to standard shotgun proteomics methods for quantitative experiments. However, most DIA methods require collecting exhaustive, sample-specific spectrum libraries with data dependent acquisition (DDA) to detect and quantify peptides. In addition to working with non-human samples, studies of splice junctions, sequence variants, or simply working with small sample yields can make developing DDA-based spectrum libraries impractical. Here we illustrate how to acquire, queue, and validate DIA data without spectrum libraries, and provide a workflow to efficiently generate DIA-only chromatogram libraries using gas-phase fractionation (GPF). We present best-practice methods for collecting DIA data using Orbitrap-based instruments, and develop an understanding for why DIA using an Orbitrap mass spectrometer should be approached differently than when using time-of-flight instruments. Finally, we discuss several methods for analyzing DIA data without libraries. Full Article
experiment Many Psychology Experiments Lack Evidence of Validity, Says Report By feeds.socialpsychology.org Published On :: 2020-05-01T04:05:06-04:00 Source: Science Daily - Top SocietyAn examination of nearly 350 published psychological experiments found that nearly half failed to show that they were based on a valid foundation of empirical evidence, suggesting that a wide swath of psychological science may be based on an "untested foundation." Full Article
experiment Cancer patients on Medicaid might not benefit from experimental treatments, study finds By www.upi.com Published On :: Thu, 30 Apr 2020 13:00:57 -0400 Cancer patients on Medicaid or who don't have insurance benefit less from experimental treatments, even if they get into clinical trials, a study published Thursday by JAMA Network Open has found. Full Article
experiment Die acute Phosphor-Vergiftung : mit besonderer Rücksicht auf Pathologie und Physiologie experimentell / bearbeitet von Ph. Munk und E. Leyden. By feedproxy.google.com Published On :: Berlin : A. Hirschwald, 1865. Full Article
experiment Die Behandlung der Wuthkrankheit : eine experimentelle Kritik des Pasteur'schen Verfahrens / von A. von Frisch. By feedproxy.google.com Published On :: Wien : L.W. Seidel, 1887. Full Article
experiment Die historische Entwicklung der experimentellen Gehirn- und Rückenmarksphysiologie vor Flourens / von Max Neuburger. By feedproxy.google.com Published On :: Stuttgart : Enke, 1897. Full Article
experiment Die Magensäure des Menschen, kritisch und experimentell / bearbeitet von F. Martius und J. Lüttke. By feedproxy.google.com Published On :: Stuttgart : F. Enke, 1892. Full Article
experiment Die multiple Fettgewebsnecrose : Klinische und experimentelle Studien / von Arthur Katz und Ferdinand Winkler ; mit einem Vorwort von Leopold Oser. By feedproxy.google.com Published On :: Berlin : S. Karger, 1899. Full Article
experiment Die Sublimatintoxication : Beitrage zur Geschichte, Klinik und pathologischen Anatomie derselben, nebst experimentellen Untersuchungen zur Theorie ihres Wesens / von E. Kaufmann. By feedproxy.google.com Published On :: Breslau : W. Koebner, 1888. Full Article
experiment Doubts of hydrophobia, as a specific disease, to be communicated by the bite of a dog ; with experiments on the supposed virus generated in that animal during the complaint termed madness ... / by Robert White. By feedproxy.google.com Published On :: London : printed for Knight and Lacey, 1826. Full Article
experiment Elementary treatise on physics, experimental and applied : for the use of colleges and schools / translated and edited from Ganot's Éléments de physique (with the author's sanction) by E. Atkinson. By feedproxy.google.com Published On :: London : Longmans, Green, 1868. Full Article
experiment The Wildcat experiment : an early test of supported work in drug abuse rehabilitation / by Lucy N. Friedman. By search.wellcomelibrary.org Published On :: Rockville, Maryland : National Institute on Drug Abuse, 1978. Full Article
experiment On the impact of selected modern deep-learning techniques to the performance and celerity of classification models in an experimental high-energy physics use case. (arXiv:2002.01427v3 [physics.data-an] UPDATED) By arxiv.org Published On :: Beginning from a basic neural-network architecture, we test the potential benefits offered by a range of advanced techniques for machine learning, in particular deep learning, in the context of a typical classification problem encountered in the domain of high-energy physics, using a well-studied dataset: the 2014 Higgs ML Kaggle dataset. The advantages are evaluated in terms of both performance metrics and the time required to train and apply the resulting models. Techniques examined include domain-specific data-augmentation, learning rate and momentum scheduling, (advanced) ensembling in both model-space and weight-space, and alternative architectures and connection methods. Following the investigation, we arrive at a model which achieves equal performance to the winning solution of the original Kaggle challenge, whilst being significantly quicker to train and apply, and being suitable for use with both GPU and CPU hardware setups. These reductions in timing and hardware requirements potentially allow the use of more powerful algorithms in HEP analyses, where models must be retrained frequently, sometimes at short notice, by small groups of researchers with limited hardware resources. Additionally, a new wrapper library for PyTorch called LUMINis presented, which incorporates all of the techniques studied. Full Article
experiment On the Optimality of Randomization in Experimental Design: How to Randomize for Minimax Variance and Design-Based Inference. (arXiv:2005.03151v1 [stat.ME]) By arxiv.org Published On :: I study the minimax-optimal design for a two-arm controlled experiment where conditional mean outcomes may vary in a given set. When this set is permutation symmetric, the optimal design is complete randomization, and using a single partition (i.e., the design that only randomizes the treatment labels for each side of the partition) has minimax risk larger by a factor of $n-1$. More generally, the optimal design is shown to be the mixed-strategy optimal design (MSOD) of Kallus (2018). Notably, even when the set of conditional mean outcomes has structure (i.e., is not permutation symmetric), being minimax-optimal for variance still requires randomization beyond a single partition. Nonetheless, since this targets precision, it may still not ensure sufficient uniformity in randomization to enable randomization (i.e., design-based) inference by Fisher's exact test to appropriately detect violations of null. I therefore propose the inference-constrained MSOD, which is minimax-optimal among all designs subject to such uniformity constraints. On the way, I discuss Johansson et al. (2020) who recently compared rerandomization of Morgan and Rubin (2012) and the pure-strategy optimal design (PSOD) of Kallus (2018). I point out some errors therein and set straight that randomization is minimax-optimal and that the "no free lunch" theorem and example in Kallus (2018) are correct. Full Article
experiment Rerandomization in $2^{K}$ factorial experiments By projecteuclid.org Published On :: Mon, 17 Feb 2020 04:02 EST Xinran Li, Peng Ding, Donald B. Rubin. Source: The Annals of Statistics, Volume 48, Number 1, 43--63.Abstract: With many pretreatment covariates and treatment factors, the classical factorial experiment often fails to balance covariates across multiple factorial effects simultaneously. Therefore, it is intuitive to restrict the randomization of the treatment factors to satisfy certain covariate balance criteria, possibly conforming to the tiers of factorial effects and covariates based on their relative importances. This is rerandomization in factorial experiments. We study the asymptotic properties of this experimental design under the randomization inference framework without imposing any distributional or modeling assumptions of the covariates and outcomes. We derive the joint asymptotic sampling distribution of the usual estimators of the factorial effects, and show that it is symmetric, unimodal and more “concentrated” at the true factorial effects under rerandomization than under the classical factorial experiment. We quantify this advantage of rerandomization using the notions of “central convex unimodality” and “peakedness” of the joint asymptotic sampling distribution. We also construct conservative large-sample confidence sets for the factorial effects. Full Article
experiment Empirical Bayes analysis of RNA sequencing experiments with auxiliary information By projecteuclid.org Published On :: Wed, 27 Nov 2019 22:01 EST Kun Liang. Source: The Annals of Applied Statistics, Volume 13, Number 4, 2452--2482.Abstract: Finding differentially expressed genes is a common task in high-throughput transcriptome studies. While traditional statistical methods rank the genes by their test statistics alone, we analyze an RNA sequencing dataset using the auxiliary information of gene length and the test statistics from a related microarray study. Given the auxiliary information, we propose a novel nonparametric empirical Bayes procedure to estimate the posterior probability of differential expression for each gene. We demonstrate the advantage of our procedure in extensive simulation studies and a psoriasis RNA sequencing study. The companion R package calm is available at Bioconductor. Full Article
experiment Bayesian Design of Experiments for Intractable Likelihood Models Using Coupled Auxiliary Models and Multivariate Emulation By projecteuclid.org Published On :: Mon, 13 Jan 2020 04:00 EST Antony Overstall, James McGree. Source: Bayesian Analysis, Volume 15, Number 1, 103--131.Abstract: A Bayesian design is given by maximising an expected utility over a design space. The utility is chosen to represent the aim of the experiment and its expectation is taken with respect to all unknowns: responses, parameters and/or models. Although straightforward in principle, there are several challenges to finding Bayesian designs in practice. Firstly, the utility and expected utility are rarely available in closed form and require approximation. Secondly, the design space can be of high-dimensionality. In the case of intractable likelihood models, these problems are compounded by the fact that the likelihood function, whose evaluation is required to approximate the expected utility, is not available in closed form. A strategy is proposed to find Bayesian designs for intractable likelihood models. It relies on the development of an automatic, auxiliary modelling approach, using multivariate Gaussian process emulators, to approximate the likelihood function. This is then combined with a copula-based approach to approximate the marginal likelihood (a quantity commonly required to evaluate many utility functions). These approximations are demonstrated on examples of stochastic process models involving experimental aims of both parameter estimation and model comparison. Full Article
experiment Constrained Bayesian Optimization with Noisy Experiments By projecteuclid.org Published On :: Wed, 13 Mar 2019 22:00 EDT Benjamin Letham, Brian Karrer, Guilherme Ottoni, Eytan Bakshy. Source: Bayesian Analysis, Volume 14, Number 2, 495--519.Abstract: Randomized experiments are the gold standard for evaluating the effects of changes to real-world systems. Data in these tests may be difficult to collect and outcomes may have high variance, resulting in potentially large measurement error. Bayesian optimization is a promising technique for efficiently optimizing multiple continuous parameters, but existing approaches degrade in performance when the noise level is high, limiting its applicability to many randomized experiments. We derive an expression for expected improvement under greedy batch optimization with noisy observations and noisy constraints, and develop a quasi-Monte Carlo approximation that allows it to be efficiently optimized. Simulations with synthetic functions show that optimization performance on noisy, constrained problems outperforms existing methods. We further demonstrate the effectiveness of the method with two real-world experiments conducted at Facebook: optimizing a ranking system, and optimizing server compiler flags. Full Article
experiment Statistical Methodology in Single-Molecule Experiments By projecteuclid.org Published On :: Tue, 03 Mar 2020 04:00 EST Chao Du, S. C. Kou. Source: Statistical Science, Volume 35, Number 1, 75--91.Abstract: Toward the last quarter of the 20th century, the emergence of single-molecule experiments enabled scientists to track and study individual molecules’ dynamic properties in real time. Unlike macroscopic systems’ dynamics, those of single molecules can only be properly described by stochastic models even in the absence of external noise. Consequently, statistical methods have played a key role in extracting hidden information about molecular dynamics from data obtained through single-molecule experiments. In this article, we survey the major statistical methodologies used to analyze single-molecule experimental data. Our discussion is organized according to the types of stochastic models used to describe single-molecule systems as well as major experimental data collection techniques. We also highlight challenges and future directions in the application of statistical methodologies to single-molecule experiments. Full Article
experiment Readiness Potential and Neuronal Determinism: New Insights on Libet Experiment By www.jneurosci.org Published On :: 2018-01-24 Karim FifelJan 24, 2018; 38:784-786Journal Club Full Article
experiment Japan's Experiment to Calculate an Asteroid's Age Was a Smashing Success By www.smithsonianmag.com Published On :: Fri, 27 Mar 2020 14:33:53 +0000 The spacecraft Hayabusa2 hurled a four-pound copper ball toward the asteroid's surface at about 4,500 miles an hour to create an artificial crater Full Article
experiment Influence of Tobacco Displays and Ads on Youth: A Virtual Store Experiment By pediatrics.aappublications.org Published On :: 2012-12-03T00:07:42-08:00 Youth exposure to retail tobacco advertisements and displays is associated with smoking initiation. The Family Smoking Prevention and Tobacco Control Act of 2009 gives states and local governments legal authority to regulate the time, place, and manner of tobacco advertising.This is the first experimental study using a virtual store environment to provide evidence that a policy banning tobacco product displays at the point of sale may deter youth from attempting to purchase tobacco products at retail stores. (Read the full article) Full Article
experiment In Vitro and In Vivo Characterization of Potent Antileishmanial Methionine Aminopeptidase-1 Inhibitors [Experimental Therapeutics] By aac.asm.org Published On :: 2020-03-16T08:17:37-07:00 Leishmania major is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL and current drug regimens present several drawbacks such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme methionine aminopeptidase-1 (MetAP1), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The in vitro antileishmanial activity of eight novel MetAP1 inhibitors (OJT001-OJT008) were investigated. Three compounds OJT006, OJT007, and OJT008 demonstrated potent anti-proliferative effect in macrophages infected with L. major amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect was diminished by almost 10-fold in transgenic L. major promastigotes overexpressing MetAP1LM in comparison to wild-type promastigotes. Furthermore, the in vivo activity of OJT006, OJT007, and OJT008 were investigated in L. major-infected BALB/c mice. In comparison to the control group, OJT008 significantly decreased footpad parasite load by 86%, and exhibited no toxicity against in treated mice. We propose MetAP1 inhibitor OJT008 as a potential chemotherapeutic candidate against CL infection caused by L. major infection. Full Article
experiment Evaluation of the efficacy of antibiotic combinations against multidrug-resistant Pseudomonas aeruginosa in automated time-lapse microscopy and static time-kill experiments [Clinical Therapeutics] By aac.asm.org Published On :: 2020-03-16T08:17:37-07:00 Objectives: Antibiotic combination therapy is used for severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria. Yet, data of which combinations are most effective is lacking. This study aimed to evaluate the in vitro efficacy of polymyxin B in combination with 13 other antibiotics against four clinical strains of MDR Pseudomonas aeruginosa.Methods: We evaluated the interactions of polymyxin B in combination with amikacin, aztreonam, cefepime, chloramphenicol, ciprofloxacin, fosfomycin, meropenem, minocycline, rifampicin, temocillin, thiamphenicol or trimethoprim by automated time-lapse microscopy using predefined cut-off values indicating inhibition of growth (≤106 CFU/mL) at 24 h. Promising combinations were subsequently evaluated in static time-kill experiments.Results: All strains were intermediate or resistant to polymyxin B, anti-pseudomonal β-lactams, ciprofloxacin and amikacin. Genes encoding β-lactamases (e.g., blaPAO and blaOXA-50) and mutations associated with permeability and efflux were detected in all strains. In the time-lapse microscopy experiments, positive interactions were found with 39 of 52 antibiotic combination/bacterial strain setups. Enhanced activity was found against all four strains with polymyxin B used in combination with aztreonam, cefepime, fosfomycin, minocycline, thiamphenicol and trimethoprim. Time kill experiments showed additive or synergistic activity with 27 of the 39 tested polymyxin B combinations, most frequently with aztreonam, cefepime, and meropenem.Conclusion: Positive interactions were frequently found with the tested combinations, also against strains that harboured several resistance mechanisms to the single drugs and with antibiotics that are normally not active against P. aeruginosa. Further study is needed to explore the clinical utility of these combinations. Full Article
experiment ZN148 - a modular synthetic metallo-{beta}-lactamase inhibitor reverses carbapenem-resistance in Gram-negative pathogens in vivo [Experimental Therapeutics] By aac.asm.org Published On :: 2020-03-16T08:17:37-07:00 Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo β-lactamase (MBL) families. The recent introduction of SBL carbapenemase-inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n=234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ~30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modelling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor, capable of operating in a functional space not presently filled by any clinically approved compound. Full Article
experiment Combination Therapy with Ibrexafungerp (formerly SCY-078), a First-in-Class Triterpenoid Inhibitor of (1->3)-{beta}-D-Glucan Synthesis, and Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis [Experimental Therapeutics] By aac.asm.org Published On :: 2020-03-16T08:17:36-07:00 Ibrexafungerp (formerly SCY-078) is a semisynthetic triterpenoid and potent (1->3)-β-D-glucan synthase inhibitor. We investigated the in vitro activity, pharmacokinetics, and in vivo efficacy of ibrexafungerp (SCY) alone and in combination with anti-mould triazole isavuconazole (ISA) against invasive pulmonary aspergillosis (IPA). The combination of ibrexafungerp and isavuconazole in in vitro studies resulted in an additive and synergistic interactions against Aspergillus spp. Plasma concentration-time curves of ibrexafungerp were compatible with linear dose proportional profile. In vivo efficacy was studied in a well established persistently neutropenic NZW rabbit model of experimental IPA. Treatment groups included untreated rabbits (UC) and rabbits receiving ibrexafungerp at 2.5(SCY2.5) and 7.5(SCY7.5) mg/kg/day, isavuconazole at 40(ISA40) mg/kg/day, or combinations of SCY2.5+ISA40 and SCY7.5+ISA40. The combination of SCY+ISA produced in vitro synergistic interaction. There was significant in vivo reduction of residual fungal burden, lung weights, and pulmonary infarct scores in SCY2.5+ISA40, SCY7.5+ISA40, and ISA40-treatment groups vs that of SCY2.5-treated, SCY7.5-treated and UC (p<0.01). Rabbits treated with SCY2.5+ISA40 and SCY7.5+ISA40 had prolonged survival in comparison to that of SCY2.5-, SCY7.5-, ISA40-treated or UC (p<0.05). Serum GMI and (1->3)-β-D-glucan levels significantly declined in animals treated with the combination of SCY7.5+ISA40 in comparison to those treated with SCY7.5 or ISA40 (p<0.05). Ibrexafungerp and isavuconazole combination demonstrated prolonged survival, decreased pulmonary injury, reduced residual fungal burden, lower GMI and (1->3)-β-D-glucan levels in comparison to those of single therapy for treatment of IPA. These findings provide an experimental foundation for clinical evaluation of the combination of ibrexafungerp and an anti-mould triazole for treatment of IPA. Full Article
experiment Fosmanogepix (APX001) is Effective in the Treatment of Pulmonary Murine Mucormycosis Due to Rhizopus arrhizus [Experimental Therapeutics] By aac.asm.org Published On :: 2020-03-23T08:47:35-07:00 Mucormycosis is a life-threatening infection with high mortality that occurs predominantly in immunocompromised patients. Manogepix (MGX) is a novel antifungal that targets Gwt1, an early step in the conserved glycosylphosphotidyl inositol (GPI) post-translational modification pathway of surface proteins in eukaryotic cells. Inhibition of inositol acylation by MGX results in pleiotropic effects including inhibition of maturation of GPI-anchored proteins necessary for growth and virulence. MGX has been previously shown to have in vitro activity against some strains of Mucorales. Here we assessed the in vivo activity of the prodrug fosmanogepix, currently in clinical development for the treatment of invasive fungal infections, against two Rhizopus arrhizus strains with high (4.0 μg/ml) and low (0.25 μg/ml) minimum effective concentration (MEC) values. In both invasive pulmonary infection models, treatment of mice with 78 mg/kg or 104 mg/kg fosmanogepix, along with 1-aminobenzotriazole to enhance the serum half-live of MGX in mice, significantly increased median survival time and prolonged overall survival by day 21 post infection when compared to placebo. In addition, administration of fosmanogepix resulted in a 1-2 log reduction in both lung and kidney fungal burden. For the 104 mg/kg fosmanogepix dose, tissue clearance and survival were comparable to clinically relevant doses of isavuconazole (ISA), which is FDA approved for the treatment of mucormycosis. These results support continued development of fosmanogepix as a first in class treatment for invasive mucormycosis. Full Article
experiment Efficacy of bedaquiline, alone or in combination with imipenem, against Mycobacterium abscessus in C3HeB/FeJ mice [Experimental Therapeutics] By aac.asm.org Published On :: 2020-04-06T08:49:26-07:00 Mycobacterium abscessus lung infections remain difficult to treat. Recent studies have recognized the power of new combinations of antibiotics such as bedaquiline and imipenem although in vitro data have questioned this combination. We report that the efficacy of the bedaquiline plus imipenem treatment relies essentially on the activity of bedaquiline in a C3HeB/FeJ mice model of infection with a rough variant of M. abscessus. The addition of imipenem contributed at clearing the infection in the spleen. Full Article
experiment Fenbendazole controls in vitro growth, virulence potential and animal infection in the Cryptococcus model [Experimental Therapeutics] By aac.asm.org Published On :: 2020-04-06T08:49:25-07:00 The human diseases caused by the fungal pathogens Cryptococcus neoformans and C. gattii are associated with high indices of mortality, and toxic and/or cost-prohibitive therapeutic protocols. The need for affordable antifungals to combat cryptococcal disease is unquestionable. Previous studies suggested benzimidazoles as promising anti-cryptococcal agents combining low cost and high antifungal efficacy, but their therapeutic potential has not been demonstrated so far. In this study, we investigated the antifungal potential of fenbendazole, the most effective anti-cryptococcal benzimidazole. Fenbendazole was inhibitory against 17 different isolates of C. neoformans and C. gattii at a low concentration. The mechanism of anti-cryptococcal activity of fenbendazole involved microtubule disorganization, as previously described for human parasites. In combination with fenbendazole, the concentrations of the standard antifungal amphotericin B required to control cryptococcal growth were lower than those required when this antifungal was used alone. Fenbendazole was not toxic to mammalian cells. During macrophage infection, the anti-cryptococcal effects of fenbendazole included inhibition of intracellular proliferation rates and reduced phagocytic escape through vomocytosis. Fenbendazole deeply affected the cryptococcal capsule. In a mice model of cryptococcosis, the efficacy of fenbendazole to control animal mortality was similar to that observed for amphotericin B. These results indicate that fenbendazole is a promising candidate for the future development of an efficient and affordable therapeutic tool to combat cryptococcosis. Full Article
experiment Repurposing the antiamoebic drug diiodohydroxyquinoline for treatment of Clostridioides difficile infections [Experimental Therapeutics] By aac.asm.org Published On :: 2020-04-06T08:49:25-07:00 Clostridioides difficile, the leading cause of nosocomial infections, is an urgent health threat worldwide. The increased incidence and severity of disease, the high recurrence rates, and the dearth of effective anticlostridial drugs have created an urgent need for new therapeutic agents. In an effort to discover new drugs for treatment of Clostridioides difficile infections (CDIs), we investigated a panel of FDA-approved antiparasitic drugs against C. difficile and identified diiodohydroxyquinoline (DIHQ), an FDA-approved oral antiamoebic drug. DIHQ exhibited potent activity against 39 C. difficile isolates, inhibiting growth of 50% and 90% of these isolates at the concentrations of 0.5 μg/mL and 2 μg/mL, respectively. In a time-kill assay, DIHQ was superior to vancomycin and metronidazole, reducing a high bacterial inoculum by 3-log10 within six hours. Furthermore, DIHQ reacted synergistically with vancomycin and metronidazole against C. difficile in vitro. Moreover, at subinhibitory concentrations, DIHQ was superior to vancomycin and metronidazole in inhibiting two key virulence factors of C. difficile, toxin production and spore formation. Additionally, DIHQ did not inhibit growth of key species that compose the host intestinal microbiota, such as Bacteroides, Bifidobacterium and Lactobacillus spp. Collectively, our results indicate that DIHQ is a promising anticlostridial drug that warrants further investigation as a new therapeutic for CDIs. Full Article
experiment Development of probiotic formulations for oral candidiasis prevention: Gellan gum as a carrier to deliver Lactobacillus paracasei 28.4 [Experimental Therapeutics] By aac.asm.org Published On :: 2020-04-06T08:49:25-07:00 Probiotics might provide an alternative approach for the control of oral candidiasis. However, studies on the antifungal activity of probiotics in the oral cavity are based on the consumption of yogurt or other dietary products, and there is a necessary to use appropriate biomaterials and specific strains to obtain probiotic formulations targeting local oral administration. In this study, we impregnated gellan gum, a natural biopolymer used as a food-additive, with a probiotic and investigated its antifungal activity against Candida albicans. Lactobacillus paracasei 28.4, a strain recently isolated from the oral cavity of a caries-free individual, was incorporated in several concentrations of gellan gum (0.6% to 1%). All tested concentrations could incorporate L. paracasei cells while maintaining bacterial viability. Probiotic/gellan formulations were stable for 7 days when stored at room temperature or 4°C. Long-term storage of bacteria-impregnated gellan gum was achieved when L. paracasei 28.4 was lyophilized. The probiotic/gellan formulations provided a release of L. paracasei cells over 24 hours that was sufficient to inhibit the growth of C. albicans with effects dependent on the cell concentrations incorporated into gellan gum. The probiotic/gellan formulations also had inhibitory activity against Candida spp. biofilms by reducing the number of Candida spp. cells (p < 0.0001), decreasing the total biomass (p = 0.0003), and impairing hyphae formation (p = 0.0002), compared to the control group which received no treatment. Interestingly, probiotic formulation of 1% w/v gellan gum provided an oral colonization of L. paracasei in mice with approximately 6 log of CFU/mL after 10 days. This formulation inhibited the C. albicans growth (p < 0.0001), prevented the development of candidiasis lesions (p = 0.0013), and suppressed inflammation (p = 0.0006) when compared to the mice not treated in the microscopic analysis of the tongue dorsum. These results indicate that gellan gum is a promising biomaterial and can be used as a carrier system to promote oral colonization for probiotics that prevent oral candidiasis. Full Article
experiment The Added Value of Longitudinal Imaging for Preclinical In vivo Efficacy Testing of Therapeutic Compounds against Cerebral Cryptococcosis [Experimental Therapeutics] By aac.asm.org Published On :: 2020-04-13T08:15:30-07:00 Brain infections with Cryptococcus neoformans are associated with significant morbidity and mortality. Cryptococcosis typically presents as meningoencephalitis or fungal mass lesions called cryptococcomas. Despite frequent in vitro discoveries of promising novel antifungals, the clinical need for drugs that can more efficiently treat these brain infections remains. A crucial step in drug development is the evaluation of in vivo drug efficacy in animal models. This mainly relies on survival studies or post-mortem analyses in large groups of animals, but these techniques only provide information on specific organs of interest at predefined time points. In this proof-of-concept study, we validated the use of non-invasive preclinical imaging to obtain longitudinal information on the therapeutic efficacy of amphotericin B or fluconazole monotherapy in meningoencephalitis and cryptococcoma mouse models. Bioluminescence imaging (BLI) enabled the rapid in vitro and in vivo evaluation of drug efficacy while complementary high-resolution anatomical information obtained by magnetic resonance imaging (MRI) of the brain allowed a precise assessment of the extent of infection and lesion growth rates. We demonstrated a good correlation between both imaging readouts and the fungal burden in various organs. Moreover, we identified potential pitfalls associated with the interpretation of therapeutic efficacy based solely on post-mortem studies, demonstrating the added value of this non-invasive dual imaging approach compared to standard mortality curves or fungal load endpoints. This novel preclinical imaging platform provides insights in the dynamic aspects of the therapeutic response and facilitates a more efficient and accurate translation of promising antifungal compounds from bench to bedside. Full Article
experiment Therapeutic efficacy of a mixed formulation of conventional and PEGylated liposomes containing meglumine antimoniate, combined with allopurinol, in dogs naturally infected with Leishmania infantum [Experimental Therapeutics] By aac.asm.org Published On :: 2020-04-13T08:15:31-07:00 Treatment of dogs naturally infected with Leishmania infantum using meglumine antimoniate (MA) encapsulated in conventional liposomes (LC) in association with allopurinol has been previously reported to promote marked reduction in the parasite burden in the main infection sites. Here, a new assay in naturally infected dogs was performed using a novel liposome formulation of MA consisting of a mixture of conventional and long-circulating (PEGylated) liposomes (LCP), with expected broader distribution among affected tissues of the mononuclear phagocyte system. Experimental groups of naturally infected dogs were as follows: LCP+Allop, receiving LCP intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose) at 4-day intervals, plus allopurinol at 30 mg/kg/12 h p.o. during 130 days; LC+Allop, receiving LC intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose), plus allopurinol during 130 days; Allop, treated with allopurinol only; non-treated control. Parasite loads were evaluated by quantitative PCR in liver, spleen and bone marrow and by immunohistochemistry in the ear skin, before, just after treatment and 4 months later. LCP+Allop and LC+Allop groups, but not the Allop group, showed significant suppression of the parasites in the liver, spleen and bone marrow 4 months after treatment, compared to the pre-treatment period or the control group. Only LCP+Allop group showed significantly lower parasite burden in the skin, in comparison to the control group. On the basis of clinical staging and parasitological evaluations, LCP formulation exhibited a more favorable therapeutic profile, when compared to LC one, being therefore promising for treatment of canine visceral leishmaniasis. Full Article
experiment Experimentally engineered mutations in a ubiquitin hydrolase, UBP-1, modulate in vivo susceptibility to artemisinin and chloroquine in Plasmodium berghei. [Mechanisms of Resistance] By aac.asm.org Published On :: 2020-04-27T08:14:56-07:00 As resistance to artemisinins (current frontline drugs in malaria treatment) emerges in south East Asia, there is an urgent need to identify the genetic determinants and understand the molecular mechanisms underpinning such resistance. Such insights could lead to prospective interventions to contain resistance and prevent the eventual spread to other malaria endemic regions. Artemisinin reduced susceptibility in South East Asia (SEA) has been primarily linked to mutations in P. falciparum Kelch-13, which is currently widely recognised as a molecular marker of artemisinin resistance. However, 2 mutations in a ubiquitin hydrolase, UBP-1, have been previously associated with artemisinin reduced susceptibility in a rodent model of malaria and some cases of UBP-1 mutation variants associating with artemisinin treatment failure have been reported in Africa and SEA. In this study, we have employed CRISPR-Cas9 genome editing and pre-emptive drug pressures to test these artemisinin susceptibility associated mutations in UBP-1 in P. berghei sensitive lines in vivo. Using these approaches, we have shown that the V2721F UBP-1 mutation results in reduced artemisinin susceptibility, while the V2752F mutation results in resistance to chloroquine and moderately impacts tolerance to artemisinins. Genetic reversal of the V2752F mutation restored chloroquine sensitivity in these mutant lines while simultaneous introduction of both mutations could not be achieved and appears to be lethal. Interestingly, these mutations carry a detrimental growth defect, which would possibly explain their lack of expansion in natural infection settings. Our work has provided independent experimental evidence on the role of UBP-1 in modulating parasite responses to artemisinin and chloroquine under in vivo conditions. Full Article
experiment Combination Therapy Using Benznidazole and Aspirin During the Acute Phase of Experimental Chagas Disease Prevents Cardiovascular Dysfunction and Decreases Typical Cardiac Lesions in the Chronic Phase [Clinical Therapeutics] By aac.asm.org Published On :: 2020-05-04T08:49:24-07:00 Chagas disease, caused by the protozoan Trypanosoma cruzi, is one of the main causes of death due to cardiomyopathy and heart failure in Latin American countries. The treatment of Chagas disease is directed at eliminating the parasite, decreasing the probability of cardiomyopathy, and disrupting the disease transmission cycle. Benznidazole (BZ) and nifurtimox (NFX) are recognized as effective drugs for the treatment of Chagas disease by the World Health Organization, but both have high toxicity and limited efficacy, especially in the chronic disease phase. At low doses, aspirin (ASA) has been reported to protect against T. cruzi infection. We evaluated the effectiveness of BZ in combination with ASA at low doses during the acute disease phase and evaluated cardiovascular aspects and cardiac lesions in the chronic phase. ASA treatment prevented the cardiovascular dysfunction (hypertension and tachycardia) and typical cardiac lesions. Moreover, BZ+ASA-treated mice had a smaller cardiac fibrotic area than that in BZ-treated mice. These results were associated with an increase in the number of eosinophils and reticulocytes and level of nitric oxide in the plasma and cardiac tissue of ASA-treated mice relative to respective controls. These effects of ASA and BZ+ASA in chronically infected mice were inhibited by pretreatment with the LXA4 receptor antagonist, Boc-2, indicating that the protective effects of ASA are mediated by ASA-triggered lipoxin. These results emphasize the importance of exploring new drug combinations for treatments of acute phase of Chagas disease that are beneficial for chronic patients. Full Article
experiment Unique experiment! Yogi Adityanath govt offers sugar in lieu of cash to sugarcane farmers By www.financialexpress.com Published On :: 2020-04-19T02:56:00+05:30 Talking to FE, principal secretary, excise and sugar industry and cane development, Sanjay R Bhoosreddy said this arrangement has been made in face of the lockdown. Full Article Economy
experiment China’s experimental spaceship works normally in orbit By www.financialexpress.com Published On :: 2020-05-07T18:22:00+05:30 The experimental spaceship was launched without crew by China's new large carrier rocket Long March-5B from the Wenchang Space Launch Centre in Hainan on Tuesday. Full Article Lifestyle Science
experiment Capsule of China’s experimental manned spaceship returns successfully By www.financialexpress.com Published On :: 2020-05-08T17:22:00+05:30 The spacecraft entered the return orbit at 12:21 pm after which its return capsule separated with its service capsule at 1:33 pm. Full Article Lifestyle Science